A ligand peptide motif selected from a cancer patient is a receptor-interacting site within human interleukin-11.
Interleukin-11 (IL-11) is a pleiotropic cytokine approved by the FDA against chemotherapy-induced thrombocytopenia. From a combinatorial selection in a cancer patient, we isolated an IL-11-like peptide mapping to domain I of the IL-11 (sequence CGRRAGGSC). Although this motif has ligand attributes, it is not within the previously characterized interacting sites. Here we design and validate in-tandem binding assays, site-directed mutagenesis and NMR spectroscopy to show (i) the peptide mimics a receptor-binding site within IL-11, (ii) the binding of CGRRAGGSC to the IL-11R alpha is functionally relevant, (iii) Arg4 and Ser8 are the key residues mediating the interaction, and (iv) the IL-11-like motif induces cell proliferation through STAT3 activation. These structural and functional results uncover an as yet unrecognized receptor-binding site in human IL-11. Given that IL-11R alpha has been proposed as a target in human cancer, our results provide clues for the rational design of targeted drugs.
Cardó-Vila
Marina
M
The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Zurita
Amado J
AJ
Giordano
Ricardo J
RJ
Sun
Jessica
J
Rangel
Roberto
R
Guzman-Rojas
Liliana
L
Anobom
Cristiane D
CD
Valente
Ana P
AP
Almeida
Fábio C L
FC
Lahdenranta
Johanna
J
Kolonin
Mikhail G
MG
Arap
Wadih
W
Pasqualini
Renata
R
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D049109:Cell Proliferation; D006801:Humans; D017370:Interleukin-11 / Q000235:genetics / Q000378:metabolism*; D053703:Interleukin-11 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D018716:Molecular Mimicry; D016297:Mutagenesis, Site-Directed; D009369:Neoplasms / Q000737:chemistry*; D010446:Peptide Fragments / Q000302:isolation & purification / Q000378:metabolism*; D011485:Protein Binding; D050796:STAT3 Transcription Factor / Q000378:metabolism
D017370:Interleukin-11; D053703:Interleukin-11 Receptor alpha Subunit; D008024:Ligands; D010446:Peptide Fragments; D050796:STAT3 Transcription Factor